Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.8 (cholinesterase)
 12,691 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Despite the amount of hard work that has gone into elucidating a toxicological basis for Gulf War Illness, we do not appear to have reached a mechanistic understanding. Investigation of long-term low-level exposure as a basis does not seem to have provided an answer. Nor does the deployment-related toxic soup idea, where exposure to a mixture of toxic chemicals not usually encountered in the same physical vicinity, seems to have explained the symptoms developed by Gulf War Veterans. The idea that an overabundance of CNS acetylcholine leftover from excessive cholinesterase inhibition is at the basis of this syndrome is intellectually appealing and offers a level of neurochemical complexity that may be just beyond the reach of our technical understanding. But no one has yet assembled a coherent mechanism from it either. It seems reasonable that chemical warfare agents were involved. They were not included in early work because it was felt that the toxicant plumes produced during the destruction of stockpiled Iraqi chemical weapons had not been large enough to cause an exposure of US forces and those of our allies. That misconception was disproven, and it is now accepted that people could very well have been exposed to low levels of massive quantities of sarin, cyclosarin, and sulfur mustard. It also seems reasonable that excess acetylcholine or neurological consequences of its presence that we do not fully understand were involved. The combination of nerve agents and the insecticidal anticholinesterases plus the pyridostigmine bromide given prophylactically were probably sufficient to cause the problem. However, the most notable thing is the result of recent work on the toxic mechanism of sulfur mustard showing that it can inhibit the microsomal electron transport chain as a result of sulfonium ion reduction to carbon free radicals by NADPH-cytochrome P450 reductase. This information was not available during the work on Gulf War Illness. So this provides an opportunity to discuss the effects of the general inhibition of the cytochrome P450 system superimposed on the conditions encountered by the participants in Desert Storm and Desert Shield as an approach to the toxicology of mixtures.
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PMID:Chemicals of military deployments: revisiting Gulf War Syndrome in light of new information. 2297 41

Parathion, a widely used organophosphate insecticide, is considered a high priority chemical threat. Parathion toxicity is dependent on its metabolism by the cytochrome P450 system to paraoxon (diethyl 4-nitrophenyl phosphate), a cytotoxic metabolite. As an effective inhibitor of cholinesterases, paraoxon causes the accumulation of acetylcholine in synapses and overstimulation of nicotinic and muscarinic cholinergic receptors, leading to characteristic signs of organophosphate poisoning. Inhibition of parathion metabolism to paraoxon represents a potential approach to counter parathion toxicity. Herein, we demonstrate that menadione (methyl-1,4-naphthoquinone, vitamin K3) is a potent inhibitor of cytochrome P450-mediated metabolism of parathion. Menadione is active in redox cycling, a reaction mediated by NADPH-cytochrome P450 reductase that preferentially uses electrons from NADPH at the expense of their supply to the P450s. Using human recombinant CYP 1A2, 2B6, 3A4 and human liver microsomes, menadione was found to inhibit the formation of paraoxon from parathion. Administration of menadione bisulfite (40mg/kg, ip) to rats also reduced parathion-induced inhibition of brain cholinesterase activity, as well as parathion-induced tremors and the progression of other signs and symptoms of parathion poisoning. These data suggest that redox cycling compounds, such as menadione, have the potential to effectively mitigate the toxicity of organophosphorus pesticides including parathion which require cytochrome P450-mediated activation.
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PMID:Vitamin K3 (menadione) redox cycling inhibits cytochrome P450-mediated metabolism and inhibits parathion intoxication. 2621 58

Accidental or intentional exposures to parathion, an organophosphorus (OP) pesticide, can cause severe poisoning in humans. Parathion toxicity is dependent on its metabolism by the cytochrome P450 (CYP) system to paraoxon (diethyl 4-nitrophenyl phosphate), a highly poisonous nerve agent and potent inhibitor of acetylcholinesterase. We have been investigating inhibitors of CYP-mediated bioactivation of OPs as a method of preventing or reversing progressive parathion toxicity. It is well recognized that NADPH-cytochrome P450 reductase, an enzyme required for the transfer of electrons to CYPs, mediates chemical redox cycling. In this process, the enzyme diverts electrons from CYPs to support chemical redox cycling, which results in inhibition of CYP-mediated biotransformation. Using menadione as the redox-cycling chemical, we discovered that this enzymatic reaction blocks metabolic activation of parathion in rat and human liver microsomes and in recombinant CYPs important to parathion metabolism, including CYP1A2, CYP2B6, and CYP3A4. Administration of menadione to rats reduces metabolism of parathion, as well as parathion-induced inhibition of brain cholinesterase activity. This resulted in inhibition of parathion neurotoxicity. Menadione has relatively low toxicity and is approved by the Food and Drug Administration for other indications. Its ability to block parathion metabolism makes it an attractive therapeutic candidate to mitigate parathion-induced neurotoxicity.
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PMID:Novel approaches to mitigating parathion toxicity: targeting cytochrome P450-mediated metabolism with menadione. 2744 53